Characterization of Glu350 as a critical residue involved in the N-terminal amine binding site of aminopeptidase N (EC 3.4.11.2): insights into its mechanism of action

Biochemistry
N LucianiM C Fournié-Zaluski

Abstract

The molecular components ensuring the strict exopeptidase action of aminopeptidase N (APN) and related zinc aminopeptidases of the M1 family have not yet been clearly established. The specific recognition of the N-terminal amino acid of the substrates by the enzymes has been proposed to involve either the complexation of the free amino group by the catalytic zinc ion or an interaction with an anionic binding site, which could be constituted by an aspartate or glutamate residue. To investigate the existence of such an ionic binding site, site-directed mutagenesis experiments have been performed on acidic residues of pig APN. Given that aminopeptidases of the M1 family are likely to have a common mechanism of action, only strictly conserved residues were mutated. As compared to the wild-type enzyme, the mutation D220E led only to slight modifications in the kinetic parameters of the enzyme and in the Ki values of various inhibitors, indicating that this residue is not critically involved in the hydrolytic mechanism. In contrast, the mutations E350Q and E350D induced a large decrease in enzyme activity, essentially due to modifications in kcat, whereas the E350A mutation led to an almost completely inactive enzyme. Moreover, among...Continue Reading

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